Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

了解拉丁裔儿童儿童急性淋巴细胞白血病风险增加

• 批准号: 10615852
• 负责人: Adam De Smith
• 金额: $ 64.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615852
• 关键词: Accounting; Acute Lymphocytic Leukemia; Admixture; Americas; Awareness; California; Cesarean section; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Cytomegalovirus Infections; Data; Environmental Exposure; Environmental Risk Factor; Epidemiology; Ethnic Origin; Etiology; European; Exhibits; Face; Future; GATA3 gene; Gene Expression; Gene Frequency; General Population; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genomic Segment; Goals; Guatemala; Heritability; Human; Immune; Immune response; Immunological Models; Incidence; Infection; Inferior; Knowledge; Latino; Latino Population; Linkage Disequilibrium; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Meta-Analysis; Modeling; Morbidity - disease rate; Native American Ancestry; Native Americans; Natural Selections; Nature; Outcome; Pediatric Oncology Group; Play; Population; Prevention; Quantitative Trait Loci; Recording of previous events; Reporting; Risk; Risk Assessment; Risk Factors; Role; Saint Jude Children' s Research Hospital; Sample Size; Survivors; Susceptibility Gene; Testing; Texas; Trees; United States; Variant; Vulnerable Populations; Weight; admixture mapping; case control; causal variant; disorder prevention; epidemiology study; ethnic disparity; genetic risk assessment; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; improved; in utero; insight; modifiable risk; novel; polygenic risk score; risk mitigation; risk prediction; risk stratification; risk variant; transcriptome; transcriptomics

ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it is still one of the leading causes of childhood death in the United States (US), and survivors face significant lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native Americans during European colonization of the Americas due to their beneficial effects on immune response to new infections. We have assembled the largest ever case-control set of childhood ALL in Latinos, including over 5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome- wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed nature of Latino genomes, and iii) a transcriptome-wide association study to identify novel loci and to pinpoint causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in terms of their association with local Native American ancestry and whether they exhibit evidence of directional natural selection on the Native American branch of the human population tree. We will also characterize the aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk models for immune-related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future approaches for childhood leukemia prevention.

抽象的 急性淋巴细胞白血病（ALL）是最常见的小儿癌，并且在治疗方面取得了进展 仍然是美国儿童死亡的主要原因之一（美国），冲浪者面临着重要的 终身治疗相关的病态。拉丁裔种族的孩子的风险最高，最快 在美国，所有的生存率都低于非拉丁裔白人；但是，这种族裔差异和 结果尚未完全理解。阐明拉丁裔儿童中所有人的风险增加可能会揭示新的见解 在拉丁裔和非拉丁裔种群中的所有病因中，可能会突出疾病的潜在途径 预防。我们假设种系遗传变异在增加的所有风险中起着至关重要的作用 拉丁美洲人，这种风险是通过美国原住民的血统所赋予的，所有风险等位基因均已在本地选择 美国人在欧洲殖民美洲殖民时期由于对免疫反应的有益影响 新感染。我们在拉丁美洲人中汇集了有史 加利福尼亚州三项独立研究的5,400例病例和27,000例对照，以及德克萨斯州的研究 肿瘤学组/st。裘德儿童研究医院和危地马拉。在我们的第一个目标中，我们将执行三个 完全发现与童年相关的新型常见风险基因座的方法：i）基因组 - 广泛的协会研究（GWAS）荟萃分析，ii）混合映射以利用最近的混合 拉丁裔基因组的​​性质和iii）一项全转录组的关联研究，以识别新的基因座并查明 已知和新型风险区域的因果基因。在我们的第二个目标中，我们将表征 他们与美国当地原住民血统的联系的条件以及是否暴露了方向的证据 自然选择人口树的美国原住民分支。我们还将表征 普通变体对儿童时期的总体影响，以及如何通过种族来综述 在拉丁美洲人和非拉丁裔白人中的所有人的多基因风险评分（PR）建模。最后，我们将合并 通过考虑普通（PRS）遗传变异的所有风险，我们进入流行病学分析的遗传发现 拉丁裔和非拉丁裔白人中与免疫相关危险因素的模型，包括剖宫产和子宫 巨细胞病毒感染，两者都对拉丁美洲人的所有风险都显示出强烈的影响，并且可能是 可修改的风险因素。这项研究的结果将阐明一般和一般的儿童病因 拉丁裔儿童中所有人的风险增加，这将有助于减轻这种种族差异并可能为未来提供信息 预防儿童白血病的方法。